Supramolecular Cylinders Target Bulge Structures in the 5' UTR of the RNA Genome of SARS-CoV-2 and Inhibit Viral Replication*

Lazaros Melidis; Harriet J Hill; Nicholas J Coltman; Scott P Davies; Kinga Winczura; Tasha Chauhan; James S Craig; Aditya Garai; Catherine A J Hooper; Ross T Egan; Jane A McKeating; Nikolas J Hodges; Zania Stamataki; Pawel Grzechnik; Michael J Hannon

doi:10.1002/anie.202104179

Supramolecular Cylinders Target Bulge Structures in the 5' UTR of the RNA Genome of SARS-CoV-2 and Inhibit Viral Replication*

Lazaros Melidis, Harriet J Hill, Nicholas J Coltman, Scott P Davies, Kinga Winczura, Tasha Chauhan, James S Craig, Aditya Garai, Catherine A J Hooper, Ross T Egan, Jane A McKeating, Nikolas J Hodges, Zania Stamataki, Pawel Grzechnik, Michael J Hannon

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Abstract

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.

Original language	English
Pages (from-to)	18144-18151
Journal	Angewandte Chemie (International Edition)
Volume	60
Issue number	33
Early online date	29 Apr 2021
DOIs	https://doi.org/10.1002/anie.202104179
Publication status	E-pub ahead of print - 29 Apr 2021

Bibliographical note

Keywords

RNA structures
SARS-CoV-2
inhibitors
metals in medicine
supramolecular chemistry

ASJC Scopus subject areas

Catalysis
Chemistry(all)

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10.1002/anie.202104179Licence: Creative Commons: Attribution (CC BY)

anie.202104179Final published version, 1.85 MBLicence: Creative Commons: Attribution (CC BY)

Understanding host factors that regulate the hepatitis B viral epigenome
Parish, J.
Medical Research Council
1/10/18 → 31/07/22
Project: Research Councils

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Melidis, L., Hill, H. J., Coltman, N. J., Davies, S. P., Winczura, K., Chauhan, T., Craig, J. S., Garai, A., Hooper, C. A. J., Egan, R. T., McKeating, J. A., Hodges, N. J., Stamataki, Z., Grzechnik, P., & Hannon, M. J. (2021). Supramolecular Cylinders Target Bulge Structures in the 5' UTR of the RNA Genome of SARS-CoV-2 and Inhibit Viral Replication*. Angewandte Chemie (International Edition) , 60(33), 18144-18151. Advance online publication. https://doi.org/10.1002/anie.202104179

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abstract = "The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.",

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Melidis, L, Hill, HJ, Coltman, NJ, Davies, SP, Winczura, K, Chauhan, T, Craig, JS, Garai, A, Hooper, CAJ, Egan, RT, McKeating, JA, Hodges, NJ , Stamataki, Z, Grzechnik, P & Hannon, MJ 2021, 'Supramolecular Cylinders Target Bulge Structures in the 5' UTR of the RNA Genome of SARS-CoV-2 and Inhibit Viral Replication*', Angewandte Chemie (International Edition) , vol. 60, no. 33, pp. 18144-18151. https://doi.org/10.1002/anie.202104179

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AU - Melidis, Lazaros

AU - Hill, Harriet J

AU - Coltman, Nicholas J

AU - Davies, Scott P

AU - Winczura, Kinga

AU - Chauhan, Tasha

AU - Craig, James S

AU - Garai, Aditya

AU - Hooper, Catherine A J

AU - Egan, Ross T

AU - McKeating, Jane A

AU - Hodges, Nikolas J

AU - Stamataki, Zania

AU - Grzechnik, Pawel

AU - Hannon, Michael J

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AB - The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.

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Supramolecular Cylinders Target Bulge Structures in the 5' UTR of the RNA Genome of SARS-CoV-2 and Inhibit Viral Replication*

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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Projects

Understanding host factors that regulate the hepatitis B viral epigenome

Cite this